The present invention relates to heteroaromatic derivatives of di-N-substituted piperazines and 1,4-di-substituted piperidines useful in the treatment of cognitive disorders, pharmaceutical compositions containing. the compounds, methods of treatment using the compounds, and to the use of said compounds in combination with acetylcholinesterase inhibitors.
Alzheimer""s disease and other cognitive disorders have received much attention lately, yet treatments for these diseases have not been very successful. According to Melchiorre et al. (J. Med. Chem. (1993), 36, 3734-3737), compounds that selectively antagonize M2 muscarinic receptors, especially in relation to M1 muscarinic receptors, should possess activity against cognitive disorders. Baumgold et al. (Eur. J. of Pharmacol., 251, (1994) 315-317) disclose 3xcex1-chloroimperialine as a highly selective m2 muscarinic antagonist.
Logemann et al (Brit. J. Pharmacol. (1961), 17, 286-296) describe certain di-N-substituted piperazines, but these are different from the inventive compounds of the present invention. Furthermore, the compounds of Logemann et al. are not disclosed to have activity against cognitive disorders.
WO 96/26196 discloses benzylpiperidines and piperazines useful as muscarinic antagonists.
The present invention relates to compounds according to the structural formula I, 
including all stereoisomers and pharmaceutically acceptable salts and solvates thereof,
wherein one of Y and Z is xe2x80x94Nxe2x80x94 and the other is xe2x80x94Nxe2x80x94 or xe2x80x94CHxe2x80x94;
X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94CH2xe2x80x94;
Q is 
R is (C1-C20)alkyl, (C3-C12)cycloalkyl, aryl, R8-aryl or heteroaryl;
R1, R2 and R3 are independently selected from the group consisting of H and (C1-C20)alkyl;
R4 is (C1-C20)alkyl, (C3-C12)cyclolalkyl or 
R5 is H, (C1-C20)alkyl, xe2x80x94C(O)(C1-C20)alkyl, R9-arylcarbonyl, xe2x80x94SO2(C1-C20)alkyl, R9-arylsulfonyl xe2x80x94C(O)O(C1-C20)alkyl, R9-aryloxy-carbonyl, xe2x80x94C(O)NH-(C1-C20)alkyl or R9-arylaminocarbonyl;
R6 is H or (C1-C20)alkyl;
R7 is H, (C1-C20)alkyl, hydroxy(C1-C20)alkyl or (C1-C20)-alkoxy(C1-C20)alkyl;
R8 is 1-3 substituents independently selected from the group consisting of H, (C1-C20)alkyl, halogen, hydroxy, (C1-C20)alkoxy or hydroxy(C1-C20)alkyl, or two adjacent R8 groups may be joined to form a (C1-C2)alkylenedioxy group; and
R9 is 1-3 substituents independently selected from the group consisting of H, (C1-C20)alkyl, halogen, amino or (C1-C20)alkylamino.
In a preferred group of compounds Z is N.
In another preferred group of compounds R is R8-substituted phenyl, especially 3,4-methylenedioxyphenyl, 3-methylphenyl, 3-chlorophenyl or 4-methoxyphenyl.
X is preferably xe2x80x94CH2xe2x80x94 or xe2x80x94SO2xe2x80x94.
Q is preferably 
R1 and R2 are each preferably H; R3 is preferably H or CH3.
In another group of preferred compounds, R4 has the formula 
wherein R7 is H or CH3; R6 is H: and R5 is R9-arylcarbonyl, preferably R9-(1-naphthyl)C(O)xe2x80x94, especially wherein R9 is fluoro, or R9-phenyl-C(O)xe2x80x94, especially wherein R9 is 2-methyl, 2-amino, 2-bromo or 2-chloro.
Another aspect of the invention is a pharmaceutical composition which comprises an effective amount of a compound having structural formula I as defined above in combination with a pharmaceutically acceptable carrier.
Another aspect of the invention is the use of a compound formula I for the preparation of a pharmaceutical composition useful in the treatment of cognitive disorders and neurodegenerative diseases such as Alzheimer""s disease.
Another aspect of this invention is a method for treating a cognitive or neurodegenerative disease comprising administering to a patient suffering from said disease an effective amount of a compound of formula I.
Except where stated otherwise the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms. Hence the definition of xe2x80x9calkylxe2x80x9d applies to xe2x80x9calkylxe2x80x9d as well as the xe2x80x9calkylxe2x80x9d portions of xe2x80x9calkoxyxe2x80x9d, etc.
Alkyl represents a straight or branched saturated hydrocarbon chain having 1 to 20 carbon atoms, more preferably 1 to 8 carbon atoms.
Cycloalkyl represents a saturated carbocyclic ring having 3 to 12 carbon atoms.
Halogen represents fluoro, chloro, bromo or iodo.
Aryl represents phenyl or naphthyl.
Heteroaryl refers to 5- to 10-membered single or benzofused aromatic rings comprising 1 to 4 heteroatoms independently selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94Nxe2x95x90, provided that the rings do not include adjacent oxygen and/or sulfur atoms. Examples of single-ring heteroaryl groups are pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl. Examples of benzofused heteroaryl groups are indolyl, quinolyl, benzo-thienyl (i.e., thianaphthenyl), benzimidazolyl, benzofuranyl, benzoxazolyl and benzofurazanyl. N-oxides of nitrogen-containing heteroaryl groups are also included. 2-, 3-, 5- and 6-positional isomers are contemplated, e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl and 6-pyridyl.
When a variable appears more than once in the structural formula, for example R8, the identity of each variable appearing more than once may be independently selected from the definition for that variable.
Compounds of this invention may exist in at least two stereo configurations based on the asymmetric carbon to which R1 is attached, provided that R1 and R2 are not identical. Also within formula I there are numerous other possibilities for stereoisomerism. All possible stereoisomers of formula I are within the scope of the invention.
Compound of formula I can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for purposes of this invention.
A compound of formula I may form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methane-sulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention.
Compounds of formula I may be produced by processes known to those skilled in the art as shown by the following reaction schemes: 
Compounds of formula IA, wherein Y is N, Z is N, Q is thienylidene, X is SO2, R4 is substituted piperidinyl and R1 and R2 are each H, can be prepared by reacting thiophenecarboxaldehyde with a 4-N-BOC-piperazine in the presence of sodium triacetoxy borohydride and acetic acid, followed by reaction with n-butyllithium and R-sulfonyl-fluoride. The BOC group is removed with acid and the resultant piperazine is reacted with a piperidone and sodium triacetoxy borohydride and acetic acid to obtain a compound of formula IA. 
Compounds of formula IB, wherein Y is N, Q is pyridazinylidene, X is SO2, R4 is substituted piperidinyl and R1 and R2 are each H, can be prepared by reacting an alkyl 6-chloropyridazine-3-carboxylate with a compound of the formula RSO2Na, reducing the resultant carboxylate to the aldehyde, and coupling an N-BOC-piperidyl substituted piperidine or piperazine compound to the aldehyde. The BOC protecting group is removed by treatment with acid, and the resultant piperidinyl compound is reacted with a compound of the formula R5COCl to obtain the desired compound of formula IB. 
Compounds of formula IC, wherein Y is CH, Q is pyridazinylidene, X is SO2, R4 is substituted piperidinyl and R1 and R2 are each H, can be prepared by reacting 3,6-diiodopyridazine with a compound of the formula RSH in the presence of a strong base such as diazabicyclo-undecane (DBU), followed by oxidation of the thiol to the sulfonyl by treatment with a reagent such a m-chloroperbenzoic acid. 4-[(4-Methylene)-piperdin-1-yl]-piperidine is treated with a reagent such as 9-borabicyclo[3.3.1]nonane (9-BBN) and the resulting trialkylborane is then reacted with the pyridazine and a palladium (0) catalyst. The BOC protecting group is removed by treatment with acid, and the resultant piperidinyl compound is reacted with a compound of the formula R5COCl to obtain the desired compound of formula IC.
To prepare compounds of formula ID, wherein Y is CH, Q is pyridazinylidene, X is S, R4 is substituted piperidinyl and R1 and R2 are each H, the Rxe2x80x94Sxe2x80x94iodopyridazine is reacted with a 4-methylenepiperidine in the presence of a palladium (0) catalyst as described above, followed by reaction with.an N-BOC-4-piperidone. The BOC-protecting group is removed and the R5 substituent is attached as described above for preparing compounds of formula IC. 
Compounds of formula IE, wherein Y is N, Q is pyridylidene, X is SO2, R4 is substituted piperidinyl and R1 and R2 are each H, can be prepared by reacting a halo-substituted nicotinic acid with a compound of the formula RSH, then reducing the acid to the corresponding alcohol and oxidizing the thiol to the corresponding sulfonyl. The resultant compound is then coupled with an N-BOC-piperidyl substituted piperidine as described for Scheme 2, and the R5substituent is attached as described for Scheme 3. 
Compounds of formula IF, wherein Y is N, Q is pyridylidene, X is SO2, R4 is substituted piperidinyl and R1 and R2 are each H, can be prepared by reacting 2,5-dibromopyridine with a compound of the formula RSO2Na and n-butyllithium, followed by coupling with an N-BOC-piperidyl substituted piperidine or piperazine, removing the BOC protecting group as described in Scheme 2 and reacting with R5COCl as described in Scheme 3 to obtain the desired compound. 
Compounds of formula IG, wherein Y is CH, Q is pyridylidene, X is SO2, R4 is substituted piperidinyl and R1 and R2 are each H, can be prepared by reacting 2,5-dibromopyridine with a compound of the formula RSO2Na, then treating the resultant compound in a manner similar to that described in Scheme 3 for preparing compounds of formula IC. 
Compounds of formula IH, , wherein Y is N, Q is pyridylidene, X is SO2, R4 is substituted piperidinyl, R1 is methyl and R2 is H, are prepared by converting 6-chloronicotinic acid to the corresponding chloro-ketone via the Weinreb amide. The chloro-ketone is reacted with RSO2Na in hot DMF, followed by enantioselective reduction using the (S)-2-methyl oxaborolidine catalyst and brace-methyl sulfide to furnish the chiral alcohol which is enriched in the R-enantiomer. The mesylate derived from the alcohol is reacted with a piperazino piperidine in refluxing acetonitrile, and removal of the BOC protecting group followed by coupling to various aromatic acids (R5CO2H) under standard conditions provides the target compounds IH.
The above reactions may be followed if necessary or desired by one or more of the following steps; (a) removing any protective groups from the compound so produced; (b) converting the compound so-produced to a pharmaceutically acceptable salt, ester and/or solvate; (c) converting a compound in accordance with formula I so produced to another compound in accordance with formula I, and (d) isolating a compound of formula I, including separating stereoisomers of formula I.
Based on the foregoing reaction sequence, those skilled in the art will be able to select starting materials needed to produce any compound in accordance with formula I.
The compounds of formula I exhibit selective m2 and/or m4 muscarinic antagonizing activity, which has been correlated with pharmaceutical activity for treating cognitive disorders such as Alzheimers disease and senile dementia.
The compounds of formula I display pharmacological activity in test procedures designated to indicate m1 and m2 muscarinic antagonist activity. The compounds are non-toxic at pharmaceutically therapeutic doses. Following are descriptions of the test procedures.
The compound of interest is tested for its ability to inhibit binding to the cloned human m1, m2, m3, and m4 muscarinic receptor subtypes. The sources of receptors in these studies were membranes from stably transfected CHO cell lines which were expressing each of the receptor subtypes. Following growth, the cells were pelleted and subsequently homogenized using a Polytron in 50 volumes cold 10 mM Na/K phosphate buffer, pH 7.4 (Buffer B). The homogenates were centrifuged at 40,000xc3x97g for 20 minutes at 4xc2x0 C. The resulting supernatants were discarded and the pellets were resuspended in Buffer B at a final concentration of 20 mg wet tissue/ml. These membranes were stored at xe2x88x9280xc2x0 C. until utilized in the binding assays described below.
Binding to the cloned human muscarinic receptors was performed using 3H-quinuclidinyl benzilate (QNB) (Watson et al., 1986). Briefly, membranes (approximately 8, 20, and 14 xcexcg of protein assay for the m1, m2, and m4 containing membranes, respectively) were incubated with 3H-QNB (final concentration of 100-200 pM) and increasing concentrations of unlabeled drug in a final volume of 2 ml at 25xc2x0 C. for 90 minutes. Non-specific binding was assayed in the presence of 1 xcexcM atropine. The incubations were terminated by vacuum filtration over GF/B glass fiber filters using a Skatron filtration apparatus and the filters were washed with cold 10 mM Na/K phosphate butter, pH 7.4. Scintillation cocktail was added to the filters and the vials were incubated overnight. The bound radioligand was quantified in a liquid scintillation counter (50% efficiency). The resulting data were analyzed for IC50 values (i.e. the concentration of compound required to inhibit binding by 50%) using the EBDA computer program (McPherson, 1985). Affinity values (Ki) were then determined using the following formula (Cheng and Prusoff, 1973);       K    i    =                    IC        50                    1        +                  [                                    concentration              ⁢                              xe2x80x83                            ⁢              of              ⁢                              xe2x80x83                            ⁢              radioligand                                      affinity              ⁢                              xe2x80x83                            ⁢                              (                                  K                  D                                )                            ⁢                              xe2x80x83                            ⁢              of              ⁢                              xe2x80x83                            ⁢              radioligand                                ]                      .  
Hence, a lower value of Ki indicates greater binding affinity.
To determine the degree of selectivity of a compound for binding the m2 receptor, the Ki value for m1 receptors was divided by the Ki value for m2 receptors. A higher ratio indicates a greater selectivity for binding the m2 muscarinic receptor.
For the compounds of this invention, the following range of muscarinic antagonistic binding activity was observed (not all compounds were tested for m3 and m4 binding activity):
m1: 96 nM to 1860 nM
m2: 1.5 nM to about 1400 nM, preferably 1.5 nM to about 600 nM
m3: 59 nM to 2794 nM
m4: 28 nM 638 nM
A preferred compound of this invention, the compound of Example 39, has an average ml antagonist binding activity of 917 and an average m2 antagonist binding activity of 1.5.
For preparing pharmaceutical compositions from the compounds of formula I, pharmaceutically acceptable, inert carriers are admixed with the active compounds. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier can be one or more substances which may also act as dilutents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; it may also be an encapsulating material.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parentertal administration. Such liquid forms include solutions, suspensions and emulsions. These particular solid form preparations are most conveniently provided in unit dose form and as such are used to provide a single liquid dosage unit.
The invention also contemplates alternative delivery systems including, but not necessarily limited to, transdermal delivery. The transdermal compositions can take the form of creams, lotions and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation such as packeted tablets, capsules and powders in vials or ampules. The unit dosage form can also be a capsule, cachet or tablet itself, or it may be the appropriate number of any of these in a packaged form.
The quantity of active compound in a unit dose preparation may be varied or adjusted from 1 mg to 100 mg according to the particular application and the potency of the active ingredient and the intended treatment. This would correspond to a dose of about 0.001 to about 20 mg/kg which may be divided over 1 to 3 administrations per day. The composition may, if desired, also contain other therapeutic agents.
The dosages may be varied depending on the requirement of the patient, the severity of the condition being treating and the particular compound being employed. Determination of the proper dosage for a particular situation is within the skill of those in the medical art. For convenience, the total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.